2023
Regulatory T cells in peripheral tissue tolerance and diseases
Cheru N, Hafler D, Sumida T. Regulatory T cells in peripheral tissue tolerance and diseases. Frontiers In Immunology 2023, 14: 1154575. PMID: 37197653, PMCID: PMC10183596, DOI: 10.3389/fimmu.2023.1154575.Peer-Reviewed Original ResearchConceptsTissue-resident TregsRegulatory T cellsT cellsResident TregsTissue TregsAutoimmune diseasesCommon human autoimmune diseasesAutoreactive T cellsHuman autoimmune diseasesNon-immune cellsNon-lymphoid tissuesTissue-resident cellsTreg poolTreg studiesEffector cytokinesPeripheral toleranceTreg functionIPEX syndromeImmune homeostasisSpecific tissue environmentsTregsSuppressive functionLoss of functionResident cellsGene signature
2020
Chapter 51 Multiple Sclerosis
Wesley S, Hafler D. Chapter 51 Multiple Sclerosis. 2020, 961-986. DOI: 10.1016/b978-0-12-812102-3.00051-8.Peer-Reviewed Original ResearchMultiple sclerosisModern treatment paradigmsAutoreactive T cellsPeripheral immune systemCentral nervous systemTreatable diseaseInflammatory processTreatment paradigmT cellsNervous systemDisease pathogenesisImmune systemUnknown originUntreatable diseaseSclerosisPathogenesisDiseaseGenetic haplotypesStrong evidenceComprehensive reviewMyelin
2019
CXCR3+ T cells in multiple sclerosis correlate with reduced diversity of the gut microbiome
Choileáin SN, Kleinewietfeld M, Raddassi K, Hafler DA, Ruff WE, Longbrake EE. CXCR3+ T cells in multiple sclerosis correlate with reduced diversity of the gut microbiome. Journal Of Translational Autoimmunity 2019, 3: 100032. PMID: 32743517, PMCID: PMC7388357, DOI: 10.1016/j.jtauto.2019.100032.Peer-Reviewed Original ResearchInflammatory T cell subsetsCentral nervous systemT cell subsetsMultiple sclerosisT cellsGut microbiomeCell subsetsCNS-reactive T cellsRelapsing-remitting MS patientsGrey matter inflammationGut-immune axisExpression of CXCR3CD8 T cellsAltered gut microbiomeAutoreactive T cellsMultiple sclerosis correlateGut microbiome compositionInflammatory subsetMS pathogenesisMS patientsTh1 phenotypeAxonal degenerationAutoimmune diseasesCascade of eventsDisease onset
2018
Regulatory T Cells: From Discovery to Autoimmunity
Kitz A, Singer E, Hafler D. Regulatory T Cells: From Discovery to Autoimmunity. Cold Spring Harbor Perspectives In Medicine 2018, 8: a029041. PMID: 29311129, PMCID: PMC6280708, DOI: 10.1101/cshperspect.a029041.Peer-Reviewed Original ResearchConceptsAutoreactive T cellsT cellsMultiple sclerosisEffector-like T cellsInterferon γ secretionEffector T cellsRegulatory T cellsTreg cell functionT-bet expressionCentral nervous systemT cell activationFunctional TregsΓ secretionProinflammatory cytokinesVitamin DAutoimmune diseasesGenetic predispositionNervous systemLoss of functionReduced suppressionConsistent findingCell functionDisease developmentActivationCells
2015
Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis
Cao Y, Goods BA, Raddassi K, Nepom GT, Kwok WW, Love JC, Hafler DA. Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis. Science Translational Medicine 2015, 7: 287ra74. PMID: 25972006, PMCID: PMC4497538, DOI: 10.1126/scitranslmed.aaa8038.Peer-Reviewed Original ResearchConceptsMyelin-reactive T cellsMultiple sclerosisT cellsHealthy controlsT cell librariesT helper cell 17Antigen-specific T cellsGene signatureMore IL-10More proinflammatory cytokinesAutoreactive T cellsIL-10 productionHuman autoimmune diseasesGranulocyte-macrophage colony-stimulating factorProduction of interferonColony-stimulating factorMyelin antigensTh17 cellsIL-10Inflammatory profileInterleukin-17Proinflammatory cytokinesAutoimmune diseasesDisease progressionHealthy subjects
2013
Regulatory T Cells in MS
Gawlik B, Hafler D. Regulatory T Cells in MS. 2013, 27-47. DOI: 10.1007/978-1-4614-7953-6_2.Peer-Reviewed Original ResearchRegulatory T cellsAutoreactive T cellsT cellsCentral nervous systemMultiple sclerosisTreg cellsHealthy individualsPathogenic autoreactive T cellsMultifocal demyelinating diseaseDemyelinating diseaseCNS lesionsMS patientsAutoimmune responseAutoimmune diseasesPeripheral bloodImmune homeostasisImmune responseNervous systemSusceptible individualsProgressive neurodegenerationDiseaseKey regulatorCellsIndividualsHigher number
2008
Multiple Sclerosis and Regulatory T Cells
Costantino CM, Baecher-Allan C, Hafler DA. Multiple Sclerosis and Regulatory T Cells. Journal Of Clinical Immunology 2008, 28: 697-706. PMID: 18763026, PMCID: PMC2752287, DOI: 10.1007/s10875-008-9236-x.Peer-Reviewed Original ResearchConceptsRegulatory T cellsCentral nervous systemAutoreactive T cellsT cellsAntigen-specific Treg cellsAutoreactive effector T cellsAutoimmune tissue damageFrequency of TregsOrgan-specific autoimmunityEffector T cellsReactive T cellsBlood-brain barrierPathology of MSIntroductionMultiple sclerosisTreg cellsMS patientsPeripheral toleranceChronic inflammationMultiple sclerosisImmune disordersNew therapiesHealthy individualsNervous systemTissue damageDisease modelsMultiple Sclerosis and Regulatory T Cells
Hutton J, Baecher-Allan C, Hafler D. Multiple Sclerosis and Regulatory T Cells. 2008, 265-277. DOI: 10.1007/978-0-387-77909-6_13.Peer-Reviewed Original ResearchRegulatory T cellsAutoreactive T cellsMultiple sclerosisT cellsAntigen-specific Treg cellsImmunopathology of MSCentral nervous system white matterAutoimmune tissue damageFrequency of TregsNervous system white matterOrgan-specific autoimmunityEffector T cellsReactive T cellsImmunosuppressive therapyTreg cellsAutoimmune processMS patientsPeripheral toleranceSpecific autoimmunityImmune disordersNew therapiesHealthy individualsB cellsWhite matterTissue damage
2004
Cross-Reactive TCR Responses to Self Antigens Presented by Different MHC Class II Molecules
Mycko MP, Waldner H, Anderson DE, Bourcier KD, Wucherpfennig KW, Kuchroo VK, Hafler DA. Cross-Reactive TCR Responses to Self Antigens Presented by Different MHC Class II Molecules. The Journal Of Immunology 2004, 173: 1689-1698. PMID: 15265898, DOI: 10.4049/jimmunol.173.3.1689.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAmino Acid SubstitutionAnimalsAntigen PresentationAutoantigensCD4 AntigensCross ReactionsEncephalomyelitis, Autoimmune, ExperimentalHLA-DR alpha-ChainsHLA-DR AntigensHLA-DRB1 ChainsHumansHybridomasL CellsLymphocyte ActivationMembrane ProteinsMiceMolecular Sequence DataMultiple Sclerosis, Relapsing-RemittingMyelin Basic ProteinPeptide FragmentsPhosphorylationProtein Processing, Post-TranslationalReceptors, Antigen, T-CellReceptors, Antigen, T-Cell, alpha-betaT-Lymphocyte SubsetsTransfectionConceptsAutoreactive T cellsMHC class II moleculesClass II moleculesT cellsSpontaneous experimental autoimmune encephalomyelitisRelapsing-remitting multiple sclerosisDifferent MHC class II moleculesExperimental autoimmune encephalomyelitisAltered peptide ligandTh cell clonesT cell hybridomasMyelin basic proteinAutoimmune encephalomyelitisMultiple sclerosisSelf antigensCD4 coreceptorRestriction elementsHealthy individualsDiseased patientsHuman TCRPatientsTCR responsesCell clonesCell hybridomasPeptide ligandsMultiple sclerosis
Hafler DA. Multiple sclerosis. Journal Of Clinical Investigation 2004, 113: 788-794. PMID: 15067307, PMCID: PMC362131, DOI: 10.1172/jci21357.Peer-Reviewed Original ResearchConceptsMultiple sclerosisT cellsAutoreactive T cellsCNS white matterHallmark of inflammationB cellsWhite matterClonal expansionMolecular pathologyRNA expressionDiseaseSclerosisInflammationComplex genetic diseasesHuman diseasesCellsAntibody productsGenetic diseasesHigh-throughput examinationTherapyPathology
2002
Inhibition of Human CD4+CD25+high Regulatory T Cell Function
Baecher-Allan C, Viglietta V, Hafler DA. Inhibition of Human CD4+CD25+high Regulatory T Cell Function. The Journal Of Immunology 2002, 169: 6210-6217. PMID: 12444126, DOI: 10.4049/jimmunol.169.11.6210.Peer-Reviewed Original ResearchMeSH KeywordsAntigensCD4-Positive T-LymphocytesCoculture TechniquesCytokinesGlucocorticoid-Induced TNFR-Related ProteinHumansImmune ToleranceInterleukin-10Lymphocyte ActivationModels, ImmunologicalReceptors, Interleukin-2Receptors, Nerve Growth FactorReceptors, Tumor Necrosis FactorSignal TransductionT-Lymphocyte SubsetsTransforming Growth Factor betaConceptsAutoreactive T cellsT cellsRegulatory cellsRegulatory T cell functionInflammatory immune responseT cell functionStrength of stimulationPathologic responseInhibition of humanMicrobial AgsResponder cellsImmune responseEffector functionsTCR stimuliTime pointsCell functionTCR signalsPotent regulatorDifferential activationExtent of suppressionStimulationActivationCellsSuppressionStimuliGAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes
Viglietta V, Kent SC, Orban T, Hafler DA. GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes. Journal Of Clinical Investigation 2002, 109: 895-903. PMID: 11927616, PMCID: PMC150925, DOI: 10.1172/jci14114.Peer-Reviewed Original ResearchMeSH KeywordsAbataceptAdultAntigens, CDAntigens, DifferentiationAutoimmunityB7-1 AntigenB7-2 AntigenCD28 AntigensCell DivisionCTLA-4 AntigenDiabetes Mellitus, Type 1FemaleGlutamate DecarboxylaseHumansImmunoconjugatesInterferon-gammaInterleukin-13IsoenzymesMaleMembrane GlycoproteinsSignal TransductionT-LymphocytesConceptsGAD65-reactive T cellsType 1 diabetesAutoreactive T cellsT cellsB7-1New-onset type 1 diabetesPancreatic islet cell antigensInsulin-dependent type 1 diabetesGlutamic acid decarboxylase 65B7-2 engagementType 1A diabetesMemory T cellsStimulation ex vivoIslet cell antigensB7-2 moleculesT cell proliferationB7-1 costimulationAutoimmune diseasesCTLA-4Healthy controlsPathogenic roleSelective blockadeCytokine secretionHuman diabetesT lymphocytes
2001
The Neuroimmunology of Multiple Sclerosis: Possible Roles of T and B Lymphocytes in Immunopathogenesis
O'connor K, Bar-Or A, Hafler D. The Neuroimmunology of Multiple Sclerosis: Possible Roles of T and B Lymphocytes in Immunopathogenesis. Journal Of Clinical Immunology 2001, 21: 81-92. PMID: 11332657, DOI: 10.1023/a:1011064007686.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsMultiple sclerosisT cellsB cellsImmunopathology of MSMyelin-reactive T cellsCentral nervous system white matterNervous system white matterAutoreactive T cellsMS immunopathologyImmunosuppressive therapyCNS pathogenesisTolerance breakdownAutoreactive cellsInflammatory diseasesPathological studiesAnimal modelsB lymphocytesWhite matterMajor mediatorDisease pathologyNonhuman primatesDiseaseEvidence supportImmunopathologySclerosis
1999
Cross-Reactivity of T-Cell Clones Specific for Altered Peptide Ligands of Myelin Basic Protein
Ausubel L, Bieganowska K, Hafler D. Cross-Reactivity of T-Cell Clones Specific for Altered Peptide Ligands of Myelin Basic Protein. Cellular Immunology 1999, 193: 99-107. PMID: 10202117, DOI: 10.1006/cimm.1998.1447.Peer-Reviewed Original ResearchConceptsT cell clonesT cellsSpecific T cell repertoireAutoreactive T cellsTh1-type cytokinesTh2-type cytokinesMultiple sclerosis patientsT cell repertoireAltered peptide ligandT cell receptor alphaPotential beneficial effectsTCR contact residuesMyelin basic proteinDownregulatory cytokinesSclerosis patientsIL-4IL-5Individual patientsReceptor alphaBeneficial effectsClonal expansionCytokinesPeptide ligandsSubstantial proliferationCross reactivity
1998
Cytokine secretion of myelin basic protein reactive T cells in patients with multiple sclerosis
Windhagen A, Anderson DE, Carrizosa A, Balashov K, Weiner HL, Hafler DA. Cytokine secretion of myelin basic protein reactive T cells in patients with multiple sclerosis. Journal Of Neuroimmunology 1998, 91: 1-9. PMID: 9846813, DOI: 10.1016/s0165-5728(98)00086-1.Peer-Reviewed Original ResearchConceptsMBP-reactive T cellsReactive T cellsChronic progressive multiple sclerosisProgressive multiple sclerosisMultiple sclerosisT cellsCytokine secretionMyelin basic proteinT cell linesNormal controlsMyelin basic protein-reactive T cellsAntigen-specific cytokine secretionMyelin-reactive T cellsNormal individualsShort-term T cell linesAutoreactive T cell linesCP MS patientsIL-12/IL-4/MBP-reactive cellsTh2-type phenotypeRR-MS patientsTh2 cytokine secretionAutoreactive T cellsMore IFN-gammaExpansion of autoreactive T cells in multiple sclerosis is independent of exogenous B7 costimulation.
Scholz C, Patton K, Anderson D, Freeman G, Hafler D. Expansion of autoreactive T cells in multiple sclerosis is independent of exogenous B7 costimulation. The Journal Of Immunology 1998, 160: 1532-8. PMID: 9570577, DOI: 10.4049/jimmunol.160.3.1532.Peer-Reviewed Original ResearchMeSH KeywordsAbataceptAntigens, CDAntigens, DifferentiationAutoantigensB7-1 AntigenB7-2 AntigenClone CellsCTLA-4 AntigenEpitopes, T-LymphocyteHumansImmunoconjugatesImmunoglobulin Fc FragmentsImmunosuppressive AgentsInterleukin-4Lymphocyte ActivationMembrane GlycoproteinsMultiple SclerosisMyelin Basic ProteinRecombinant Fusion ProteinsT-Lymphocyte SubsetsTetanus ToxoidThymidineConceptsCD4 T cellsMultiple sclerosisT cellsB7-1Myelin basic proteinPathogenesis of MSMyelin-reactive T cellsPeripheral blood T cellsB7-2 engagementAutoreactive T cellsBlood T cellsAbsence of costimulationCentral nervous systemAntigen-specific signalT cell activationMS patientsB7 costimulationInflammatory diseasesTetanus toxoidB7-2Normal controlsNormal subjectsCostimulatory signalsNervous systemCell activationExtreme Th1 bias of invariant Vα24JαQ T cells in type 1 diabetes
Wilson S, Kent S, Patton K, Orban T, Jackson R, Exley M, Porcelli S, Schatz D, Atkinson M, Balk S, Strominger J, Hafler D. Extreme Th1 bias of invariant Vα24JαQ T cells in type 1 diabetes. Nature 1998, 391: 177-181. PMID: 9428763, DOI: 10.1038/34419.Peer-Reviewed Original ResearchConceptsType 1 diabetesT cellsMajor histocompatibility complexIL-4T cell-mediated destructionNon-diabetic siblingsAutoreactive T cellsHigher serum levelsTwins/tripletsType1 diabetic patientsDiabetic patientsSerum levelsTh1 biasDiabetic siblingsImmune systemTissue damageIncomplete concordanceDiabetesHistocompatibility complexIDDMIdentical twinsIFNDiseaseRiskCells
1997
Direct Ex Vivo Analysis of Activated, Fas-sensitive Autoreactive T Cells in Human Autoimmune Disease
Bieganowska K, Ausubel L, Modabber Y, Slovik E, Messersmith W, Hafler D. Direct Ex Vivo Analysis of Activated, Fas-sensitive Autoreactive T Cells in Human Autoimmune Disease. Journal Of Experimental Medicine 1997, 185: 1585-1594. PMID: 9151896, PMCID: PMC2196290, DOI: 10.1084/jem.185.9.1585.Peer-Reviewed Original ResearchConceptsAutoreactive T cellsT cellsMultiple sclerosisPersistent T cellsT cell frequenciesHuman autoimmune diseasesSubpopulation of patientsT cell clonesT cell receptorSingle T cellsMyelin basic proteinAutoimmune diseasesAutoantigenic peptidesAntigen stimulationDirect exCell frequencyTCR transcriptsFlow cytometryCell receptorCell clonesBeta chainHigh frequencyCell deathBasic proteinChain transcripts
1996
Activation of human T cell lymphotropic virus type I-infected T cells is independent of B7 costimulation.
Scholz C, Freeman GJ, Greenfield EA, Hafler DA, Höllsberg P. Activation of human T cell lymphotropic virus type I-infected T cells is independent of B7 costimulation. The Journal Of Immunology 1996, 157: 2932-8. PMID: 8816399, DOI: 10.4049/jimmunol.157.7.2932.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalAntigen-Presenting CellsAntigens, CDAutoimmunityB7-1 AntigenB7-2 AntigenBase SequenceCD28 AntigensCHO CellsClone CellsCricetinaeCricetulusEnzyme ActivationHLA-DR AntigensHLA-DRB1 ChainsHuman T-lymphotropic virus 1HumansInterferon-gammaInterleukin-4Interleukin-5Janus Kinase 3Lymphocyte ActivationMembrane GlycoproteinsMolecular Sequence DataMyelin Basic ProteinProtein-Tyrosine KinasesSignal TransductionT-Lymphocyte SubsetsTransfectionConceptsHuman T-cell lymphotropic virus type ILymphotropic virus type IB7 costimulationT cell clonesT cellsB7-1Virus type IIL-4IL-5B7-2IFN-gammaAutoreactive T cell responsesCell clonesAg-specific signalAutoimmune-like diseaseT cell responsesAutoreactive T cellsHTLV-I infectionB7-2 costimulationB7-2 moleculesUninfected T cellsType IAutoimmune responseB7 expressionCytokine secretionAntigen‐specific TGF‐β1 Secretion with Bovine Myelin Oral Tolerization in Multiple Sclerosis
FUKAURA H, KENT S, PIETRUSEWICZ M, KHOURY S, WEINER H, HAFLER D. Antigen‐specific TGF‐β1 Secretion with Bovine Myelin Oral Tolerization in Multiple Sclerosis. Annals Of The New York Academy Of Sciences 1996, 778: 251-257. PMID: 8610978, DOI: 10.1111/j.1749-6632.1996.tb21133.x.Peer-Reviewed Original ResearchConceptsRelapsing-remitting MS patientsHuman autoimmune diseasesOral tolerizationMultiple sclerosisAutoimmune diseasesT cell linesMS patientsCytokine secretionT cellsAutoreactive T-cell populationsAutoreactive T cellsT cell populationsT-cell fractionCNS white matterFed patientsIL-4Inflammatory responseΒ1 secretionIFN-gammaTolerizationWhite matterPatientsSclerosisBovine myelinSecretion